FtsZ as an Antibacterial Target: Status and Guidelines for Progressing This Avenue

Abstract

The disturbing increase in the number of bacterial pathogens that are resistant to multiple, or sometimes all, current antibiotics highlights the desperate need to pursue the discovery and development of novel classes of antibacterials. The wealth of knowledge available about the bacterial cell division machinery has aided target-driven approaches to identify new inhibitor compounds. The main division target being pursued is the highly conserved and essential protein FtsZ. Despite very active research on FtsZ inhibitors for several years, this protein is not yet targeted by any commercial antibiotic. Here, we discuss the suitability of FtsZ as an antibacterial target for drug development and review progress achieved in this area. We use hindsight to highlight the gaps that have slowed progress in FtsZ inhibitor development and to suggest guidelines for concluding that FtsZ is actually the target of these molecules, a key missing link in several studies. In moving forward, a multidisciplinary, communicative, and collaborative process, with sharing of research expertise, is critical if we are to succeed.

Benzodioxane‐Benzamides as Antibacterial Agents: Computational and SAR Studies to Evaluate the Influence of the 7‐Substitution in FtsZ Interaction

“…The two in vitro assays are the ones widely used to investigate changes in FtsZ enzymatic function, as suggested by Kusuma and Tripathy in recent reviews on this topic. [30,31] FtsZ inhibition of PC190723 and of other FtsZ inhibitors was confirmed in this way.…”

“…Besides, we confirmed FtsZ as the target of this class of derivatives using a GTPase activity assay and a polymerization activity assay. The two in vitro assays are the ones widely used to investigate changes in FtsZ enzymatic function, as suggested by Kusuma and Tripathy in recent reviews on this topic . FtsZ inhibition of PC190723 and of other FtsZ inhibitors was confirmed in this way.…”

Targeting Bacterial Cell Division: A Binding Site-Centered Approach to the Most Promising Inhibitors of the Essential Protein FtsZ

“…Several experimental procedures should be performed to properly ensure that FtsZ is the primary target of a putative inhibitor. All the possible assays, together with their aims and the most significant examples, were outstandingly summarized in the review of Kusuma and co-workers [13]. Following their guideline, the FtsZ inhibitory evaluation can be achieved with both in vitro and in vivo assays.…”

“…As a result, in order to confirm the binding of compounds with FtsZ and its consequent inhibition, any researcher should proceed using a multi-assay approach, which combines both in vitro and in vivo experiments ( Figure 2). As suggested by Kusuma and co-workers [13], the first step to evaluate the cell division inhibition should be the phenotype evaluation. This quick and simple experiment allows easily excluding non-active compounds and, in contrast, could give an initial strong proof of division inhibition.…”

Structure-Guided Design of a Fluorescent Probe for the Visualization of FtsZ in Clinically Important Gram-Positive and Gram-Negative Bacterial Pathogens

“…We have previously developed prodrugs of benzamide FtsZ inhibitors ( PC190723 and TXA707 ) that are highly efficacious against infections caused by methicillin-resistant Staphylococcus aureus (MRSA) 9–11 . One of these prodrugs ( TXA709 ) is currently in phase I clinical trials 6 . To date, the bulk of the compounds that have been validated as FtsZ inhibitors both in vitro with purified FtsZ and in bacterial cells are associated with potent activity against staphylococci, Mycobacterium tuberculosis , and select other Gram-positive bacterial strains, but weaker or no activity against Gram-negative species 8,11–13,23,24 .…”